Atherosclerosis is a chronic inflammatory process that results in the formation of unstable coronary lesions which can rupture suddenly, causing cute coronary events. New approaches to the stabilization, regression, and prevention of vulnerable coronary atherosclerotic lesions are still needed. High density lipoprotein (HDL) cholesterol levels are strongly inversely associated with CHD risk and represent an attractive target for the development of new therapies for atherosclerotic cardiovascular disease. Apolipoprotein A-I (apoA-I) is the major protein in HDL and has been demonstrated to inhibit progression of atherosclerosis in animals. Apolipoprotein E (apoE) is a multi-functional protein associated with HDL that has also been recognized to have potent anti-atherogenic properties. Using liver-directed genes transfer with second generation recombinant adenoviruses, we have demonstrated that liver-derived apoA-I and apoE accumulate in pre-existing atherosclerotic lesions in mice and induce significant regression and morphologic changes consistent with lesion "stabilization." These observations suggest that this approach could be developed as a novel systemic therapy for progressive atherosclerotic cardiovascular disease refractory to conventional therapy. In this project, we will determine whether the acute stabilization of atherosclerotic lesions induced by second generation adenoviruses expressing murine apoE and murine apoA-I result in long-term effects on atherosclerotic lesions in mice. We will optimize the use of recombinant adeno-associated viruses for the hepatic expression of apoE and apoA-I in mice. We will test the hypothesis that the optimal approach is the combination of adenovirus (for acute stabilization) followed by rAAV (for long term maintenance and prevention). In parallel, we will explore the potential of using a fully-deleted adenovirus for expression of murine apoE and/or apoA-I and modulating atherosclerosis. Finally, we will extend our observations in mice into a rabbit model of atherosclerosis. Our long term goal is to gain insight into the role of gene transfer of HDL- associated proteins in the modulation of established atherosclerosis and into the mechanisms by which these proteins modulate and prevent atherosclerosis.